Flumazenil was first synthesised in 1979 and is an example of an imidazobenzodiazepine derivative. Its pKA value in weak base is 1.7. Flumazenil is a basic drug and insoluble in water, but slightly soluble in acidic aqueous solutions. For example, the solubility of flumazenil at pH 1.2 is 3 mg/ml and at pH 7.5, flumazenil has a solubility of only 0.6 mg/ml. The drug has a well established place in the treatment of benzodiazepine overdose as it has been commercially available as an intravenous injection containing 5 or 10 ml aqueous solution (0.5 g/ml at pH 4).
Flumazenil reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABAA receptor. In addition, intravenous administration of flumazenil may also be effective in overdoses of non-benzodiazepine sleep enhancers in high short term doses, and has been used in hepatic encephalopathy, though results have been mixed.
The onset of action of intravenous delivery of flumazenil is rapid and usually effects are seen within one to two minutes. The peak effect is seen at about six to ten minutes. In general, the recommended dose for adults is an intravenous dose of 200 μg every one to two minutes until the effect is seen, to a maximum of 3 mg per hour. Since many benzodiazepines have a longer half life than flumazenil, repeated doses of flumazenil may be required to prevent recurrent symptoms of over-dosage. Furthermore, patients that are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon administration of flumazenil.
It is commonly known that flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in humans. Furthermore, it has been suggested that flumazenil does not antagonise the central nervous system effects of drugs affecting GABA neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Bolus infusion of flumazenil of 2 mg in 10 minutes can act as a specific panicogen in subjects with panic disorder [Bell C et al., (2000). Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J. Psycho-pharmacol. 16: 5-14] However, intravenous infusion of flumazenil has no effect on social anxiety [Coupland N J et al., (2000). Flumazenil challenge in social phobia. Depress Anxiety. 11:27-30] or alcohol-dependent subjects [Potokar J et al., (1997). Flumazenil in alcohol withdrawal: a double-blind placebo-controlled study. Alcohol Alcohol. 32: 605-611].
One of the problems associated with the treatment of patients in need of flumazenil is compliance and the difficulties associated with intravenous infusion. That is, the very short half life and low oral bioavailability of the compound limit the use of flumazenil to clinical settings, such as hospitals and drug clinics, which are often avoided by patients in need of treatment. Furthermore, venous access may be compromised due to the patient's state of physical health. Therefore, there exists a need to treat diseases or medical disorders in a less invasive manner.
The applicant of the present invention has surprisingly found that low doses of imidazobenzodiazepine derivatives, such as flumazenil alone or in combination with receptor antagonists have unexpected effects on the central nervous system. In addition, a method for the administration of flumazenil alone or in combination with antagonists has been developed which allows for a patient to be treated either on a patient controlled basis or over a continuous period of time via subcutaneous administration.